Diabetic nephropathy (DN) is among the most lethal complications that occur in patients with both type 1 and type 2 diabetes. It is characterized as a major glomerulopathy that develops to glomerulosclerosis, leading ultimately to end-stage renal disease (ESRD). Despite considerable attention from both clinicians and basic scientists, the prevalence of ESRD in diabetic patients is increasing dramatically. Thus, understanding the pathogenesis of DN is crucial to developing new approaches for its prevention and treatment. Recent investigations have revealed that injuries to podocytes play a critical role in the development of diabetic nephropathy. These highly differentiated glomerular epithelial cells and their foot processes comprise the slit diaphragm, a barrier for repelling serum proteins on the surface of glomerular capillaries. Podocyte injury may produce micro-albuminuria, an early feature of DN. The molecular mechanisms by which diabetes causes podocyte injury remain unclear. Furthermore, whether podocyte injury is a cause or a consequence of DN also continues to be uncertain. The TSC-mTORC1 pathway is an evolutionarily conserved signaling pathway that regulates growth and survival. This pathway responds to nutrients such as glucose and growth factors, and in turn controls a wide array of cellular processes such as translation, transcription, and autophagy. We have shown that activation of the mTORC1 pathway plays a critical role in diabetes-dependent podocyte injury. Our studies indicate that all pathological alterations present in a mouse model of DN, including podocyte morphological changes, glomerular basement membrane (GBM) thickening, proteinuria, glomerular hypertrophy, and mesangial expansion, can be prevented by treatment with rapamycin, a specific mTOR inhibitor. Moreover, podocyte-specific mTORC1 activation in a non-diabetic mouse recapitulated podocyte injury and other features of DN in a rapamycin-sensitive manner. These observations indicate a critical role for the site-specific activation of mTORC1 in podocytes during the development of DN. To explore this possibility in greater detail, I will focus on understanding how the TSC-mTORC1 pathway is regulated in podocytes during diabetes;the molecular mechanisms underlying mTORC1-dependent podocyte injury;and whether activation of mTORC1 in podocytes is sufficient to produce DN. I anticipate that these studies will reveal much about the molecular mechanisms underlying podocyte injury in DN, and provide important clues for developing new approaches to the treatment of this debilitating disease. PUBLIC HEALTH RELEVANCE: Recent investigations have revealed that injuries to podocytes play a critical role in the development of diabetic nephropathy (DN). The goal of this proposal is to elucidate the role of mTOR pathway as a molecular mechanism underlying podocyte injury in DN. Completion of this project will not only reveal a novel molecular mechanism for podocyte injury but also set the stage for additional studies to explore new therapeutic approaches to the treatment of DN.